ABSTRACT
Aim:
The study aimed to know the changes in spirometry parameters in chronic smokers and evaluate how the presence of type 2 diabetes mellitus (T2DM) affects their lung function.
Materials and Methods:
A prospective, cross-sectional, observational study was done for 12 months at a tertiary care hospital in the western region of Maharashtra State in India. Two groups of patients and one group of healthy volunteers aged 18 years or more were studied (with 50 in each group, n = 150). Group A consisted of smokers with T2DM, Group B- smokers without T2DM and Group 3- healthy controls who were non-smokers and non-diabetic. Spirometry was done for the following parameters: forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC ratio, and peak expiratory flow (PEF) and results compared between the three groups.
Results:
The mean age of the participants was 51.13 ± 10.74 years. There were 137 (91.3%) males and 13 (8.6%) females. Among the enrolled subjects, 66% had smoked for more than ten years. All spirometry parameters were significantly different across all three groups. When the spirometry parameters were compared between smokers with and without T2DM, all the parameters were significantly decreased (P < 0.05). FEV1 and FEV1/FVC were significantly decreased in T2DM patients with HbA1c >7%.
Conclusion:
The presence of T2DM in smokers significantly affects their pulmonary function tests. Uncontrolled T2DM (HbA1c >7%) can result in increased abnormality in the spirometry parameters studied. Thus, adequate glycemic control and cessation of smoking can be beneficial for the improvement of lung functions in smokers.
Keywords: Diabetes mellitus, glycated hemoglobin, smokers, spirometry, type 2
Introduction
Diabetes mellitus is a common endocrine disease due to absolute or relative insulin deficiency. Pulmonary diabetic microangiopathy is an under-recognized complication because a substantial loss of the pulmonary microvascular bed can be tolerated without developing dyspnea.[1,2]
Cigarette smoking carries a major health risk of the development of chronic respiratory diseases and abnormal lung functions.[3,4] Thus, both smoking and T2DM cause deterioration of respiratory functions.
Most of the studies on diabetes mellitus and pulmonary function abnormalities have excluded smokers. The current study aims to compare the difference in spirometry parameters of smokers with diabetes mellitus with that of smokers without diabetes mellitus which will help in knowing how the presence of T2DM can further worsen the already compromised lung functions in smokers and in introducing several preventive measures to limit the lung damage in these patients.
Materials and Methods
This cross-sectional observational study was conducted at a tertiary care hospital in Western Maharashtra, India, for 12 months. A total of 844 patients were referred for spirometry for various reasons. All eligible study participants above the age of 18 years were enrolled. Figure 1 shows the patient selection algorithm. The study participants were divided into the following three groups-
Figure 1.
Patient selection algorithm
-
Group A consisted of 50 patients who had been smoking (cigarettes, pipes, and bidis) for more than one year with diabetes mellitus. The diabetic patients were identified on the following basis:
- Patients on oral hypoglycemic drugs/insulin
- Random blood sugar ≥200 mg/dl
- Fasting blood sugar ≥126 mg/dl and/or post-prandial blood sugar ≥140 mg/dl
- HbA1c ≥6.5%
Group B included 50 patients who had been smoking for more than one year without diabetes mellitus.
Group C had 50 non-smokers without diabetes mellitus (healthy controls)
The following patients were excluded from the study age < 18 years; patients who had any acute or chronic respiratory disease like tuberculosis, pneumonia, or bronchial asthma; known cases of malignancy or neuro-muscular diseases, cardiac diseases, recent major chest or abdominal surgeries; patients who were unable to perform spirometry/unwilling to take part in the study.
Study procedure
The study was conducted after the Institutional Ethics Committee approval (Approval letter No I.E.S.C./15/2021) and after taking the patient’s written and informed consent. The following data were collected from all the study subjects—age, gender, occupation, history regarding the use of tobacco, duration since he/she began smoking, type of tobacco smoked (cigarette, bidi, etc.), packs per day, number of pack years (number of packs of cigarettes/day multiplied by the duration of smoking in years), duration since diabetes mellitus was diagnosed, and type of treatment being taken for diabetes mellitus.
Spirometry was done on all of the participants. Before performing spirometry, participants were thoroughly explained the process and encouraged to practice the maneuver. It was done before and after inhaling 400 mcg of the bronchodilator Salbutamol. COSMED Pulmonary Function Equipment-Quark PFT 2008 was used for the spirometry. As per standard procedure, the test was performed with the study participant in a sitting position and he/she was advised to take a deep breath (maximum inspiration), followed by a hard and forcible expiration into the spirometer. After relaxation, the tests were performed three times. The tests were repeated three times after relaxation, and the best of the three approved readings was picked for analysis. The metrics listed below were measured using the American Thoracic Society Criteria—[5]forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), peak expiratory flow (PEF), and Tiffeneau–Pinelli index (FEV1/FVC). Fasting and post-prandial blood sugar levels were measured by the hexokinase method, and glycosylated hemoglobin (HbA1c) was measured by high-performance liquid chromatography method (HPLC).
Statistical analysis
The collected data was entered into an MS Excel worksheet and analyzed using the SPSS version 17. The continuous variables were expressed as mean ± standard deviation and statistical tests (Student’s t test, ANOVA test) were applied. All tests were two-tailed, and the results were expressed at 95% confidence level. A P value of less than 0.05 was considered statistically significant.
Results
A total of 150 study participants were divided into three groups—groups A, B, and C. Table 1 shows the demographic parameters of the study subjects. The majority of the study subjects were males (90%), and cigarettes were the most common form of smoking used in groups A and B. The age range of smokers with T2DM was 38–71 years and that of smokers without T2DM was 28–72 years. The majority of the study subjects were in the sixth decade of life and were unskilled workers. Out of 100 total smokers, 66 (66%) smoked for more than 10 years with an average duration of smoking being above 13 years in both diabetic and non-diabetic groups. There was no significant difference between the average duration and pack-years of smoking between the smokers with and without diabetes (P > 0.05). The overall average pack years of smoking by all the patients in groups A and B were 9.81 ± 4.74 years. In Group A, the mean fasting blood glucose level was 148.75 ± 46.25 mg/dL, the postprandial blood glucose level was 236.4 ± 58.65 mg/dL, and the mean HbA1c was 7.01 ± 0.69%. All patients with T2DM were on treatment for the same. The majority were on oral hypoglycemic agents (OHA) (70%), and the remaining were on insulin ± OHAs (30%).
Table 1.
Demographic data of study participants
| Parameters | Cases | Controls Non-smokers, non-diabetics (Group C) (n=50) |
Significance | |
|---|---|---|---|---|
|
| ||||
| Smokers with diabetes mellitus (Group A) (n=50) | Smokers without diabetes mellitus (Group B) (n=50) | |||
| Gender | ||||
| Male | 45 (90%) | 46 (92%) | 46 (92%) | |
| Female | 5 (10%) | 4 (8%) | 4 (8%) | |
| Age | 51.3±10.69 | 50.90±10.70 | 51.2±11.37 | |
| Average duration of smoking (Years) | 13.55±5.53 | 13.25±7.46 | - | P=0.87 (NS) (Student’s t test) |
| Type of smoking | ||||
| Cigarette | 48 (96%) | 46 (92%) | - | |
| Bidi | 2 (4%) | 4 (8%) | ||
| Others | - | - | ||
| Average pack years of smoking | 10.35±4.57 | 9.37±4.86 | - | P=0.56 (NS) (Student’s t test) |
*NS=Not significant
When the spirometry parameters of Group A, Group B, and Group C were compared using the one-way ANOVA test [Table 2], all the parameters were significantly different across the three groups (P < 0.05). Table 3 shows the comparison of spirometry parameters between diabetic and non-diabetic smokers. All spirometry parameters were significantly worse in smokers with T2DM than in smokers without T2DM (P < 0.05).
Table 2.
Spirometry parameters of Group A, Group B, and Group C
| Spirometry parameters | Cases | Controls Group C Non- smokers, non-diabetic, healthy subjects |
Statistical test ANOVA Test P (Significance) |
|
|---|---|---|---|---|
|
| ||||
| Group A Smokers with diabetes mellitus | Group B Smokers without diabetes mellitus | |||
| FEV1 (L) | ||||
| (pre-b) | 1.02±0.29 | 1.50±0.42 | 2.31±0.56 | <0.05 (S) |
| (post-b) | 1.08±0.33 | 1.56±0.41 | 2.32±0.53 | <0.05 (S) |
| FVC (L) | ||||
| (pre-b) | 1.53±0.27 | 1.98±0.43 | 2.74±0.71 | <0.05 (S) |
| (post-b) | 1.61±0.34 | 2.12±0.51 | 2.78±0.68 | <0.05 (S) |
| FEV1/FVC (%) | ||||
| (pre-b) | 64.67±9.27 | 72.41±7.36 | 84.47±4.03 | <0.05 (S) |
| (post-b) | 64.93±9.40 | 72.84±8.04 | 84.71±3.82 | <0.05 (S) |
| PEF (L/s) | ||||
| (pre-b) | 2.91±1.08 | 4.24±1.15 | 6.92±1.68 | <0.05 (S) |
| (post-b) | 2.96±1.19 | 4.41±1.26 | 7.02±1.54 | <0.05 (S) |
*FVC=Forced vital capacity, FEV1=Forced expiratory volume in the first second, PEF=Peak expiratory flow, FEV1/FVC=Tiffeneau–Pinelli index, pre-b-pre-bronchodilation, post-b-post-bronchodilation, L=Liter, L/s=Liters/sec, S=Significant
Table 3.
Comparison of spirometry parameters between Group A and Group B
| Spirometry parameters (Pre-bronchodilation) | Smokers with T2DM (Group A) | Smokers without T2DM (Group B) | Statistical test Student’s t-test P (Significance) |
|---|---|---|---|
| FEV1 (L) | 1.02±0.29 | 1.50±0.42 | =0.00013 (S) |
| FVC (L) | 1.53±0.27 | 1.98±0.43 | =0.00027 (S) |
| FEV1/FVC (%) | 64.67±9.27 | 72.41±7.36 | =0.0028 (S) |
| PEF (L/s) | 2.91±1.08 | 4.24±1.15 | =0.00013 (S) |
FEV1=Forced expiratory volume in the first second, FVC=Forced vital capacity, FEV1/FVC=Tiffeneau–Pinelli index, L=Liter, L/s=Liters/sec, PEF=Peak expiratory flow, S=Significant
Group A patients were further divided into two groups based on HbA1c levels—those with HbA1c <7% were grouped as well-controlled T2DM and those with HbA1c ≥7% as inadequately controlled T2DM. Table 4 shows the comparison of spirometry parameters between these two groups, and it was found that FEV1 and FEV1/FVC were significantly decreased in patients with HbA1c ≥7% (P < 0.05) but FVC was not significantly different.
Table 4.
Comparison of spirometry parameters according to HbA1c levels
| Spirometry parameters (Pre- bronchodilation) | HbA1c <7% (n=13) | HbA1c ≥7% (n=37) | Student’s t-test P (Significance) |
|---|---|---|---|
| FEV1 (L) | 1.24±0.29 | 0.93±0.27 | =0.03 (S) |
| FVC (L) | 1.59±0.33 | 1.49±0.28 | =0.53 (NS) |
| FEV1/FVC (%) | 77.73±3.34 | 61.33±10.72 | =0.0038 (S) |
| PEF (L/s) | 2.46±1.11 | 3.51±0.71 | =0.06 (NS) |
FEV1=Forced expiratory volume in the first second, FVC=Forced vital capacity, FEV1/FVC=Tiffeneau–Pinelli index, L=Liter, L/s=Liters/sec, PEF=Peak expiratory flow, S=Significant, NS=Not significant
Discussion
Pulmonary dysfunction is common in smokers as well as patients suffering from T2DM. The current study was done to determine whether the presence of T2DM in smokers worsens their Spirometry parameters or not. Pulmonary dysfunction in T2DM is due to microangiopathic damage to the lungs and autonomic dysfunction of the phrenic nerve causing reduced tone of the diaphragm and other respiratory muscles, thus causing alteration of spirometry parameters.[6] Smoking is associated with severe health consequences, one of them being the development of chronic obstructive pulmonary disease. Nicotine in cigarette smoke causes inflammation and damages the airways, thereby affecting lung function.[7]
Over the years, the consumption of tobacco and cigarettes has increased multiple-fold. A meta-analysis conducted by Pahari S et al. reported that the current tobacco usage in any form, among Indians between the period 2010–2022 was 35.25% and the prevalence of tobacco smoking was 18.91%.[8] According to the Global Adult Tobacco Survey (GATS-2, 2016-17) 10.7% of adults in India currently smoke tobacco. The prevalence of smoking was found to be higher in men (19%) in comparison with women (2%).[9] This was similar to the findings of the current study. The majority of our study participants were more than 50 years old. With age, the lung becomes stiffer, the alveoli can lose their shape and the diaphragm may become weaker, thus contributing to the decreased lung functions.[10] With age, lifestyle disorders like hypertension and obesity can also coexist with T2DM which may affect the lungs. The combination of aging, smoking, and the presence of T2DM can further compromise lung functions.[11]
Type of occupation can also affect the frequency of smoking and the glycemic control in an individual. In a large US-based study, it was reported that unemployed individuals and manual laborers had higher chances of becoming smokers than employed and professional individuals.[12] Long working hours and those engaged in agricultural activities tend to have poorer glycemic control as compared to those with white-collar occupations.[13] In the current study, the majority of the participants were either agricultural workers or had blue-collar jobs with an average HbA1c greater than 7%. This finding matched with a study done by Davila EP et al.[14] Poor glycemic control, advancing age and prolonged smoking in T2DM leads to early onset and rapid worsening of T2DM related complications including pulmonary dysfunction.[15]
The inhaled tobacco product most frequently used in India is Bidi. Bidi use is more prevalent in rural India. The majority of the patients in our study were cigarette smokers. Ours was an urban study, and the proportion of cigarette smoking is much higher than bidi smoking in urban areas.[16] Studies have reported that the FVC, FEV1, ratio of FEV1/FVC, and PEFR are decreased in smokers in comparison with non-smokers.[17,18] It is one of the most serious and prevalent risk factors for the development of chronic lung diseases. All spirometry parameters were significantly worse in smokers (with and without T2DM) compared to non-smokers in the current study. Various studies have also been conducted to understand the effect of diabetes mellitus on lung functions and a majority of them have found that there is a significant reduction of FVC and FEV1 in patients with T2DM in comparison with non-diabetic, healthy patients.[19,20,21] However, most of these studies have reported the impact of only smoking or only diabetes mellitus on lung functions. Our study differed from previous research as we specifically investigated the cumulative impact of both smoking and T2DM on lung functions.
All the spirometry parameters—FEV1, FVC, FEV1/FVC, and PEF—were significantly decreased in smokers with T2DM, compared to smokers without T2DM. There was no significant difference in smoking duration or pack-years of smoking between smokers with and without T2DM. Thus, we can infer that any worsening of the PFT parameters between these two groups is primarily due to the impact of T2DM on already compromised lung functions. Kinney GL et al. found that in smokers who are diabetic (who do not have an obstructive disease) FVC and FEV1 were significantly lower than controls.[22] In another Indian study of 60 patients to know the impact of T2DM on PFTs in COPD patients, it was found that the FVC, FEV1, and FEV1/FVC were significantly decreased in diabetic COPD patients compared to the non-diabetic COPD patients.[23] Our study findings that diabetes significantly affects the spirometry parameters of smokers corroborate with these studies.
In T2DM patients, the HbA1c is a measure of the recent past glycemic control. Maan HB et al. found that the HbA1c had a significant inverse correlation with FEV1/FVC between well-controlled diabetics (HbA1c <7%) and inadequately controlled diabetics (HbA1c ≥7%).[24] Similar findings were present in our study. The impact of smoking on glycemic control in individuals with T2DM is a relatively underexplored area of research, and the findings may be conflicting. Smoking has been associated with a worsening of insulin resistance in patients with T2DM and quitting smoking may help improve glycemic control.[25] Both the tobacco and the T2DM epidemics are threats to global public health and are important causes of pulmonary morbidity.
This study is indicative of accelerated worsening of lung functions in chronic smokers who are diabetics and hence indicates that there is an increased need for screening of lung functions in chronic smokers who develop diabetes or vice versa. The small sample size, fewer female participants, and urban setting of the place where the study was carried out were the few limitations of the current study. In the times ahead, more studies on a large scale are required to study the superadded effects of diabetes mellitus on the lungs of smokers.
Thus, the results of the current study further consolidate the pressing need for the early intervention and counselling by the primary care physicians who are often the first point of contact for majority of T2DM patients who are smokers for smoking cessation and other lifestyle changes and can help in reversing certain damages caused by either of the factors.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
ICMR.
References
- 1.Shah SH, Sonawane P, Nahar P, Vaidya S, Salvi S. Pulmonary function tests in type 2 diabetes mellitus and their association with glycemic control and duration of the disease. Lung India. 2013;30:108–12. doi: 10.4103/0970-2113.110417. doi:10.4103/0970-2113.110417. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Klein OL, Krishnan JA, Glick S, Smith LJ. Systematic review of the association between lung function and type 2 diabetes mellitus. Diabet Med. 2010;27:977–87. doi: 10.1111/j.1464-5491.2010.03073.x. doi:10.1111/j. 1464-5491.2010.03073.x. [DOI] [PubMed] [Google Scholar]
- 3.Kenfield SA, Wei EK, Rosner BA, Glynn RJ, Stampfer MJ, Colditz GA. Burden of smoking on cause-specific mortality: Application to the nurses'health study. Tob Control. 2010;19:248–54. doi: 10.1136/tc.2009.032839. doi:10.1136/tc. 2009.032839. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Tantisuwat A, Thaveeratitham P. Effects of smoking on chest expansion, lung function, and respiratory muscle strength of youths. J Phys Ther Sci. 2014;26:167–70. doi: 10.1589/jpts.26.167. doi:10.1589/jpts. 26.167. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. Standardization of spirometry 2019 update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019;200:e70–88. doi: 10.1164/rccm.201908-1590ST. doi:10.1164/rccm. 201908-1590ST. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Kalappan M, Rajendran K, Suthakaran PK, Thangaraj P, Ganapathy G, Karuthodiyil R. Study on comparison of pulmonary function tests among diabetic and non-diabetic patients in a tertiary care hospital. Int J Adv Med. 2016;3:938–41. [Google Scholar]
- 7.Lugade AA, Bogner PN, Thatcher TH, Sime PJ, Phipps RP, Thanavala Y. Cigarette smoke exposure exacerbates lung inflammation and compromises immunity to bacterial infection. J Immunol. 2014;192:5226–35. doi: 10.4049/jimmunol.1302584. doi:10.4049/jimmunol. 1302584. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Pahari S, Barman D, Talukdar R. Tobacco usage in India: A meta-analysis of evidence drawn from regional studies between 2010 and 2022. Trop Med Int Health. 2023;28:699–709. doi: 10.1111/tmi.13924. doi:10.1111/tmi. 13924. [DOI] [PubMed] [Google Scholar]
- 9.Tata Institute of Social Sciences (TISS), Mumbai and Ministry of Health and Family Welfare, Government of India. Global Adult Tobacco Survey GATS 2 India 2016-17 [Google Scholar]
- 10.Sharma G, Goodwin J. Effect of aging on respiratory system physiology and immunology. Clin Interv Aging. 2006;1:253–60. doi: 10.2147/ciia.2006.1.3.253. doi:10.2147/ciia.2006.1.3.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Petrie JR, Guzik TJ, Touyz RM. Diabetes, hypertension, and cardiovascular disease: Clinical insights and vascular mechanisms. Can J Cardiol. 2018;34:575–84. doi: 10.1016/j.cjca.2017.12.005. doi:10.1016/j.cjca. 2017.12.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Waldron I, Lye D. Employment, unemployment, occupation, and smoking. Am J Prev Med. 1989;5:142–9. [PubMed] [Google Scholar]
- 13.Lee J, Kim HR, Jang TW, Lee DW, Jeong C, Kang MY. Poor glycemic control in workers with diabetes mellitus in relation to long working hours: A cross-sectional study. Ind Health. 2020;58:451–9. doi: 10.2486/indhealth.2020-0037. doi:10.2486/indhealth. 2020-0037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Davila EP, Florez H, Trepka MJ, Fleming LE, Niyonsenga T, Lee DJ, et al. Long work hours is associated with suboptimal glycemic control among US workers with diabetes. Am J Ind Med. 2011;54:375–83. doi: 10.1002/ajim.20923. doi:10.1002/ajim.20923. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Rawashdeh A, Alnawaiseh N. Effects of cigarette smoking and age on pulmonary function tests in≥40 years old adults in Jordan. Biomed Pharmacol J. 2018;11:789–93. [Google Scholar]
- 16.Gupta V, Yadav K, Anand K. Patterns of tobacco use across rural, urban, and urban-slum populations in a north Indian community. Indian J Community Med. 2010;35:245–51. doi: 10.4103/0970-0218.66877. doi:10.4103/0970-0218.66877. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Kumar A, Priyadarshini H, Prathyusha KP. A comparative study of pulmonary function tests in tobacco smokers and non smokers. Int J Biol Med Res. 2013;4:3570–2. [Google Scholar]
- 18.Bano R, Ahmad N, Mahagaonkar AM, Latti RG. Study of lung functions in smokers and non-smokers in rural India. Indian J Physiol Pharmacol. 2011;55:84–8. [PubMed] [Google Scholar]
- 19.Sharma A, Sharma A, Chauhan R. Spirometric lung functions in type 2 diabetes mellitus: A hospital-based study. Cureus. 2023;15:e38919. doi: 10.7759/cureus.38919. doi:10.7759/cureus.38919. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Irfan M, Jabbar A, Haque AS, Awan S, Hussain SF. Pulmonary functions in patients with diabetes mellitus. Lung India. 2011;28:89–92. doi: 10.4103/0970-2113.80314. doi:10.4103/0970-2113.80314. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Kumari R, Goswami P, Bhattacharyya DK, Kakati S. Pulmonary function test by spirometry in patients with diabetes mellitus and correlation with disease duration and Hba1c level: A case control study. Int J Contemp Med Res. 2021;8:1–5. [Google Scholar]
- 22.Kinney GL, Black-Shinn JL, Wan ES, Make B, Regan E, Lutz S, et al. Pulmonary function reduction in diabetes with and without chronic obstructive pulmonary disease. Diabetes Care. 2014;37:389–95. doi: 10.2337/dc13-1435. doi:10.2337/dc13-1435. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Adiody S, Narmadha MP, Menon AR, Varghese PR. Impact of diabetes mellitus on pulmonary function tests in COPD patients. Int J Contemp Med Res. 2017;4:795–7. [Google Scholar]
- 24.Maan HB, Meo SA, Al Rouq F, Meo IMU, Gacuan ME, Alkhalifah JM. Effect of glycated hemoglobin (HbA1c) and duration of disease on lung functions in type 2 diabetic patients. Int J Environ Res Public Health. 2021;18:6970. doi: 10.3390/ijerph18136970. doi:10.3390/ijerph18136970. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Campagna D, Alamo A, Di Pino A, Russo C, Calogero AE, Purrello F, et al. Smoking and diabetes: Dangerous liaisons and confusing relationships. Diabetol Metab Syndr. 2019;11:85. doi: 10.1186/s13098-019-0482-2. doi:10.1186/s13098-019-0482-2. Erratum in: Diabetol Metab Syndr 2023;15:117. [DOI] [PMC free article] [PubMed] [Google Scholar]

